Endothelial cells (ECs) are among the first cells to die acutely after contusive spinal cord injury (SCI), triggering secondary degeneration, including axon and myelin loss. Remaining and newly angiogenic blood vessels are leaky and dysfunctional, enabling detrimental leukocyte infiltration. We made substantial progress in understanding these vascular responses and targeting them with pharmacological treatments for neuroprotection. For example, i.v. treatments with the Tie2 ligand angiopoietin-1 (Ang1) plus the [unreadable]v[unreadable]3/[unreadable]5[unreadable]1 integrin agonist C16 provide high levels of functional recovery, vascular and tissue protection, and reduced inflammation. Key to the success is the i.v. route, which is rapid and clinically highly relevant. However, it is essential that we find additional therapeutic methods or targets as we rescue less than half of the blood vessels and white matter and no long-projecting descending pathways. This is critically important when considering translation of these EC-targeted treatments to humans, which do not recover neurological function even remotely as well as mice do. We suggest that this is possible by adding the neuroprotective effects of protein tyrosine phosphatase (PTP) inhibition, which rescues axons projecting through the injury site. To identify additional opportunities for neuroprotective treatments Aim 1 will determine whether PTP inhibition can further enhance the effect of C16+Ang1 on EC survival and tissue sparing and whether EC sparing mediates rescue of long-projecting axons, and whether this involves VE-PTP, which normally inactivates Tie2. We have also found new avenues to study and modulate angiogenesis, which we now recognize as one of the critical and beneficial EC response to SCI. We developed a novel microvascular purification method and using EC- specific microarrays, identified thrombospondin-1 (TSP-1), a potent anti-angiogenic factor which also induces EC apoptosis, as the most highly upregulated gene (60-fold) in these vessels 24 hours post-SCI. Aim 2 will delineate the role of CD36 and CD47, two domain-specific TSP-1 EC receptors, in mediating vascular responses after SCI. We will take both gain and loss of function pharmacological approaches in vivo. Subsequent in vitro experiments will address mechanism(s) of successful treatments. These 2 revised aims will identify additional molecular targets and much better EC-targeted intravenous treatments for improved tissue locomotor function following traumatic SCI.